Individual differences in alcohol responses may identify individuals at risk for developing alcohol use disorders (AUDs). Research in this field has predominantly excluded individuals with psychiatric disorders limiting the generalizability of this association. Bipolar disorder has the highest rate of AUDs of any psychiatric diagnosis yet there is a paucity of study investigating mechanisms that contribute to this comorbidity. Given the high genetic load of both bipolar disorder and AUDs, familial risk factors likely contribute to the emergence of their comorbidity. Several of the genes showing overlap in bipolar disorder and AUDs have also been suggested to underlie individual differences in response to alcohol. Individuals with a family history of AUDs exhibit altered responses to alcohol, which may identify those at increased risk for developing AUDs. It is unknown if familial risk for bipolar disorder is associated with altered sensitivity to alcohol which in turn may contribute to elevated risk for developing comorbid AUDs. This R21 application proposes a preliminary study to begin dissecting how familial risk factors contribute to individual differences in risk for developing AUDs in bipolar disorder. Specifically, responses to alcohol and associated alcohol use patterns will be investigated in 100 young adults (equally divided by familial risk for bipolar disorder but not AUDs, familial risk for bipolar disorder and AUDS, familial risk for AUDs but not bipolar disorder, and typically developing age- and sex- matched young adults). We hypothesize that familial risk for bipolar disorder is associated with altered responses to alcohol and, through that mechanism, increased risk for AUDs. This will be tested through two aims: (Aim 1) identify differences in responses to alcohol (specifically differences in transdermal alcohol concentration [TAC], heart rate, body sway, and self-report of intoxication) in individuals with familial risk for bipolar disorder and/or AUDs and (Aim 2) assess relations between responses to alcohol and alcohol use patterns in individuals with familial risk for bipolar disorder. In the proposed research, young adults will be clinically phenotyped and family history and recent alcohol and drug use patterns assessed. Then following standard beverage administration procedures in a simulated bar lab, participants will complete measures of physiological and subjective responses to alcohol while under the influence of alcohol or a placebo (within-person, counter-balanced) and wearing an alcohol biosensor that continuously measures TAC. We predict familial risk for bipolar disorder, compared to familial risk for AUDs and no familial risk subgroup will show a shorter time to reach peak TAC, higher peak TAC, and faster absorption and elimination rates. We predict differences in TAC variables will be associated with risky alcohol use patterns in individuals with familial risk for bipolar disorder. Differences in other measures of response to alcohol will be investigated and relations with TAC measures examined. This R21 award is a critical first-step to identifying mechanisms that may contribute to elevated risk for AUDs in bipolar disorder. Findings could inform new, specific targets for early detection of risk, prevention, and treatment that are more specific and effective in bipolar disorder.